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Featured researches published by Lihren Chen.
BMC Neuroscience | 2012
John C. McKew; Katherine L. Lee; Lihren Chen; Richard Vargas; James D. Clark; Cara Williams; Valerie Clerin; Suzana Marusic; Kevin Pong
BackgroundActivation of phospholipase A2 (PLA2) and the subsequent metabolism of arachidonic acid (AA) to prostaglandins have been shown to play an important role in neuronal death in neurodegenerative disease. Here we report the effects of the prion peptide fragment HuPrP106-126 on the PLA2 cascade in primary cortical neurons and translocation of cPLA2 to neurites.ResultsExposure of primary cortical neurons to HuPrP106-126 increased the levels of phosphorylated cPLA2 and caused phosphorylated cPLA2 to relocate from the cell body to the cellular neurite in a PrP-dependent manner, a previously unreported observation. HuPrP106-126 also induced significant AA release, an indicator of cPLA2 activation; this preceded synapse damage and subsequent cellular death. The novel translocation of p-cPLA2 postulated the potential for exposure to HuPrP106-126 to result in a re-arrangement of the cellular cytoskeleton. However p-cPLA2 did not colocalise significantly with F-actin, intermediate filaments, or microtubule-associated proteins. Conversely, p-cPLA2 did significantly colocalise with the cytoskeletal protein beta III tubulin. Pre-treatment with the PLA2 inhibitor, palmitoyl trifluoromethyl ketone (PACOCF3) reduced cPLA2 activation, AA release and damage to the neuronal synapse. Furthermore, PACOCF3 reduced expression of p-cPLA2 in neurites and inhibited colocalisation with beta III tubulin, resulting in protection against PrP-induced cell death.ConclusionsCollectively, these findings suggest that cPLA2 plays a vital role in the action of HuPrP106-126 and that the colocalisation of p-cPLA2 with beta III tubulin could be central to the progress of neurodegeneration caused by prion peptides. Further work is needed to define exactly how PLA2 inhibitors protect neurons from peptide-induced toxicity and how this relates to intracellular structural changes occurring in neurodegeneration.
Journal of Medicinal Chemistry | 2008
John C. McKew; Katherine L. Lee; Marina W.H. Shen; Paresh Thakker; Megan A. Foley; Mark L. Behnke; Baihua Hu; Fuk-Wah Sum; Steve Tam; Yonghan Hu; Lihren Chen; Steven J. Kirincich; Ronald S. Michalak; Jennifer R. Thomason; Manus Ipek; Kun Wu; Lane Wooder; Manjunath K. Ramarao; Elizabeth Murphy; Debra G. Goodwin; Leo M. Albert; Xin Xu; Frances Donahue; M. Sherry Ku; James C. Keith; Cheryl Nickerson-Nutter; William M. Abraham; Cara Williams; Martin Hegen; James D. Clark
The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
Bioorganic & Medicinal Chemistry | 2003
Neal Green; Jason Shaoyun Xiang; Jing Chen; Lihren Chen; Audrey Molina Davies; Dave Erbe; Steve Tam; James F. Tobin
The interaction of co-stimulatory molecules on T cells with B7 molecules on antigen presenting cells plays an important role in the activation of naive T cells. Consequently, agents that disrupt these interactions should have applications in treatment of transplant rejection as well as autoimmune diseases. To this end, specific small molecule inhibitors of human B7.1 were identified and characterized. Herein, we report the identification of potent small molecule inhibitors of the B7.1-CD28 interaction. In a high-throughput screen we identified several leads that prevented the interaction of B7.1 with CD28 with activities in the nanomolar to low micromolar range. One of these, the dihydrodipyrazolopyridinone 1, was subsequently shown to bind the V-like domain of human B7.1 at equimolar stoichiometry. With this as a starting point, we report here the synthesis and initial in vitro structure-activity relationships of a series of these compounds.
Journal of Medicinal Chemistry | 2008
Jason Shaoyun Xiang; Zhao-Kui Wan; Huan-Qiu Li; Manus Ipek; Eva Binnun; Jill Nunez; Lihren Chen; John C. McKew; Tarek S. Mansour; Xin Xu; Vipin Suri; May Tam; Yuzhe Xing; Xiangping Li; Seung Hahm; James Tobin; Eddine Saiah
11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11beta-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11beta-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.
Journal of Medicinal Chemistry | 2009
Lihren Chen; Weiheng Wang; Katherine L. Lee; Marina W.H. Shen; Elizabeth Murphy; Wen Zhang; Xin Xu; Steve Tam; Cheryl Nickerson-Nutter; Debra G. Goodwin; James D. Clark; John C. McKew
The cPLA(2)alpha inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD(7.4). To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA(2)alpha inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA(2)alpha inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD(7.4) values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.
Die Pharmazie | 1996
Jasbir S. Seehra; Yibin Xiang; Jean Bemis; John Mckew; Neelu Kaila; Lihren Chen
Journal of Medicinal Chemistry | 2007
Katherine L. Lee; Megan A. Foley; Lihren Chen; Mark L. Behnke; Frank Lovering; Steven John Kirincich; Weiheng Wang; Jaechul Shim; Steve Tam; Marina W.H. Shen; SooPeang Khor; Xin Xu; Debra G. Goodwin; Manjunath K. Ramarao; Cheryl Nickerson-Nutter; Frances Donahue; M. Sherry Ku; and James D. Clark; John C. McKew
Bioorganic & Medicinal Chemistry | 2008
Katherine L. Lee; Mark L. Behnke; Megan A. Foley; Lihren Chen; Weiheng Wang; Richard Vargas; Jill Nunez; Steve Tam; Nevena Mollova; Xin Xu; Marina W.H. Shen; Manjunath K. Ramarao; Debra G. Goodwin; Cheryl Nickerson-Nutter; William M. Abraham; Cara Williams; James D. Clark; John C. McKew
Archive | 2007
Jason Shaoyun Xiang; Eddine Saiah; Steve Tam; John C. McKew; Lihren Chen; Manus Ipek; Katherine L. Lee; Huan-Qui Li; Jianchang Li; Wei Li; Tarek S. Mansour; Vipin Suri; Richard Vargas; Yuchuan Wu; Zhao-Kui Wan; Jinbo Lee; Eva Binnun; Douglas P. Wilson
Journal of Medicinal Chemistry | 2002
Neelu Kaila; Lihren Chen; Bert E. Thomas; Desiree Tsao; Steve Tam; Patricia W. Bedard; Raymond T. Camphausen; and Juan C. Alvarez; Giliyar V. Ullas